PANCREATITE CRONICE LA COPIL

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1 2 REFERATE GENERALE PANCREATITE CRONICE LA COPIL Dr. Gabriela Leşanu 1, Dr. Daniela Păcurar 1, Dr. Cristina Becheanu 1, Dr. Raluca Vlad 1, Dr. Mariana Coman 2, Dr. Dumitru Orăşeanu 1 1 Spitalul Clinic de Urgenţă pentru Copii Grigore Alexandrescu, Bucureşti 2 Spitalul Clinic de Urgenţă pentru Copii Marie Curie, Bucureşti REZUMAT Pancreatita cronică (PC) se caracterizează prin infl amaţie cronică, fi broză progresivă, durere şi pierderea funcţiilor endocrină şi exocrină. În 1999 a fost formulată ipoteza episodului santinelă de pancreatită acută (sentinel acute pancreatitis event - SAPE), care sugerează că episodul iniţial de pancreatită generat de stres metabolic sau oxidativ este urmat de infl amaţie recurentă sau cronică care produce fi broză. Celulele stelate pancreatice au fost identifi cate ca având rol cheie în progresia pancreatitei cronice şi în dezvoltarea fi brinogenezei. PC este o afecţiune heterogenă cu un spectru clinic care include: durere, afectarea funcţiilor endocrine şi exocrine pancreatice şi variate complicaţii ce implică organele adiacente pancreasului. Pentru a stabili diagnosticul de PC la adult sunt necesare dovezi histologice, morfologice sau o combinaţie de argumente clinice, funcţionale şi morfologice. Recent, Grupul Internaţional de Studiu pentru Pancreatită la Copil (International Study Group Of Pediatric Pancreatitis) a propus următoarele criterii de diagnostic pentru PC: a) dureri abdominale tipice plus aspecte imagistice caracteristice sau (b) insufi cienţă pancreatică exocrină plus aspecte imagistice sau (c) insufi cienţă pancreatică endocrină plus aspecte imagistice. Etiologia PC este diferită la pacienţii pediatrici comparativ cu pacienţii adulţi. În ultimiii ani s-au realizat progrese remarcabile în cunoaşterea pancreatitei ereditare şi pancreatitei autoimune. În etiologia pancreatitelor cronice diagnosticate la copil pot fi identifi cate cauze obstructive. Pancreatitele cronice obstructive sunt determinate de factori mecanici congenitali sau dobîndiţi. Abordarea terapeutică include măsuri conservatoare (analgetice, antiinfl amatorii, substituţie enzimatică), intervenţii endoscopice, precum şi proceduri chirurgicale. Colangiopancreatografi a retrogradă endoscopică este utilizată ca procedură terapeutică pentru boala biliopancreatică ce generează pancreatita recurentă sau cronică. La cazurile de PC la care modalităţile terapeutice menţionate se dovedesc inefi ciente se poate recurge la pancreatectomie totală cu autotransplant portal de insule pancreatice. Cuvinte cheie: pancreatită, celule stelate pancreatice INTRODUCERE Pancreatita se caracterizează prin inflamaţia pancreasului şi poate fi considerată o entitate cu spectru clinic larg ce variază de la un episod izolat de pancreatită acută la pancreatită cronică (PC) (1). Pancreatita poate fi acută, cu debut brusc şi durată sub 6 luni; este adesea generată de o cauză specifică, dar severitatea şi durata sunt variabile. Pancreatita acută este un proces reversibil, fără efecte de durată asupra parenchimului şi funcţiilor pancreasului. Pancreatita recurentă se caracterizează prin apariţia repetată a unor episoade de pancreatită ( 2 episoade) după perioade de remisiune şi indică o susceptibilitate sau o problemă intrinsecă. PC are durata mai mare de 6 luni şi se caracterizează prin inflamaţie cronică, fibroză progresivă, durere şi pierderea funcţiilor endocrină şi exocrină. PC se constituie la cazurile la care inflamaţia şi distrucţia pancreatică nu se remit complet (2). La adult, incidenţa PC este 3,5-10/ locuitori în SUA (2) şi 7,74/ locuitori în Franţa (3). Incidenţa PC la copil nu este cunoscută. PATOGENEZĂ În 1999 a fost formulată ipoteza episodului santinelă de pancreatită acută (sentinel acute pancreatitis event SAPE), care sugerează că epi sodul iniţial de pancreatită generat de stres metabolic sau oxidativ este urmat de inflamaţie recurentă sau cronică care produce fibroză (4). Celulele stelate Adresa de corespondenţă: Dr. Gabriela Leşanu, Spitalul Clinic de Urgenţă pentru Copii Grigore Alexandrescu, Blv. Iancu de Hunedoara Nr , Bucureşti 236

2 237 pancreatice au fost identificate ca având rol cheie în progresia pancreatitei cronice şi în dezvoltarea fibrinogenezei, acestea fiind activate în timpul episoadelor repetate necro-inflamatorii sau direct de factorii toxici. Masamune (2008) a demonstrat că în celulele stelate pancreatice NADPH oxidaza (nico tinamid adenin dinucleotid fosfat oxidaza) generează oxigen reactiv care determină activarea acestor celule (5). În timpul episoadelor de pancreatită, celulele stelate, macrofagele şi limfocitele activate infiltrează parenchimul, produc citokine şi depozitează mici cantităţi de colagen. La unii pacienţi celulele inflamatorii şi celulele stelate rămân active şi în cele din urmă determină fibroza glandei. Inhibarea sau modelarea celulelor stelate pancreatice ar putea reprezenta o modalitate de intervenţie la pacienţii cu PC în viitor. Michalski şi colab. (2007) au studiat cocultura celulelor stelate pancreatice cu celule mononucleare din sângele periferic şi au demonstrat creşterea nivelului de fibronectină secretată de către celulele mononucleare, precum şi creşterea nivelului IL-6, chemokinei MCP-1 (monocyte chemotactic protein-1), TGF-beta şi proteinelor ECM (extracellular matrix) din celulele stelate pancreatice (6). Astfel, infiltrarea crescută cu celule mononucleare care poate fi observată în PC ar putea acţiona ca un trigger (pentru celulele stelate pancreatice) care să iniţieze fibroza şi inflamaţia. DIAGNOSTIC POZITIV PC este o afecţiune heterogenă cu un spectru clinic care include durere, afectarea funcţiilor endocrine şi exocrine pancreatice şi variate complicaţii ce implică organele adiacente pancreasului. Bolnavii pot prezenta un simptom izolat sau o combinaţie de simptome, consecinţă a perturbării funcţiilor pancreatice. Cel mai frecvent simptom este durerea abdominală ce apare intermitent sau este persistentă, cronică şi este variabilă în ceea ce priveşte intensitatea, de la durere uşoară la durere severă. Insuficienţa pancreatică exocrină determină mal digestie cu meteorism abdominal, diaree cu steatoree. Afectarea nutriţională cu deficite de proteine şi vitamine evidenţiate prin examene de laborator sunt, de asemenea, consecinţe ale maldigestiei. Insuficienţa pancreatică endocrină se manifestă iniţial cu intoleranţă la glucoză (niveluri inadecvat crescute de glucoză în sânge), dar 48% dintre pacienţii adulţi cu pancreatită cronică dezvoltă diabet zaharat tip I. Stabilirea diagnosticului de pancreatită cronică implică cel puţin un criteriu clinic (durere, episoade de pancreatită acută, steatoree, diabet zaharat) sau complicaţii bine definite ale pancreatitei cronice (obstrucţia/stenoza ductelor biliare cu icter, co lestază, obstrucţie/stenoză duodenală, pseudochist pancreatic, ascită pancreatogenă, alte complicaţii legate de organele vecine). Aceste criterii clinice se asociază cu demonstrarea prin studii imagistice a unor anomalii bine definite (Tabelul 1). TABELUL 1. Criterii imagistice în PC Modificări ale ductelor neregularităţi ale canalului pancreatic principal sau ale ramurilor secundare colaterale ± defecte de umplere intraductală calculi obstrucţia (stenoza) canalului pancreatic dilataţia canalului pancreatic Modificări ale parenchimului mărirea generală sau focală a glandei chisturi calcificări Pentru a stabili diagnosticul de PC sunt necesare dovezi histologice, morfologice sau o combinaţie de argumente clinice, funcţionale şi morfologice. Studiile imagistice sunt efectuate la majoritatea pacienţilor şi evidenţiază modificările morfologice, dar dovezile histologice sunt rar obţinute. Ecografia, computer tomografia (CT), colangiopancreatografia RM (magnetic resonance cholangiopancreatography MRCP) şi colangiopancreatografia retrogradă endoscopică (endoscopic retrograde cholangio-pancreatography ERCP) evaluează morfologia pancreatică. ERCP reprezintă investigaţia de elecţie pentru evaluarea ductelor pancreatice. Explorarea funcţiei pancreatice poate susţine diagnosticul de PC prin evidenţierea insuficienţei pancreatice. Recent, Grupul Internaţional de Studiu pentru Pancreatită la Copil (International Study Group Of Pediatric Pancreatitis) a propus următoarele criterii de diagnostic pentru PC: a) dureri abdominale tipice plus aspecte imagistice caracteristice sau (b) insuficienţă pancreatică exocrină plus aspecte imagistce sau (c) insuficienţă pancreatică endocrină plus aspecte imagistice (7). FORME ETIOLOGICE DE PANCREATITĂ Etiologia PC este diferită la pacienţii pediatrici (Tabelul 2) comparativ cu pacienţii adulţi. La copil sunt mai frecvent implicate cauze genetice şi anomalii structurale biliopancreatice. Re cent a fost definită pancreatita autoimună, entitate rar întâlnită la copil.

3 238 TABELUL 2. Etiologia PC la copil Cauze gene ce Autoimune Cauze obstruc ve anatomice/dobândite Cauze toxice, metabolice Idiopa că Mutaţii PRSS1 Mutaţii SPINK1 Mutaţii CFTR Pancreatita autoimună izolată Pancreatita autoimună asociată altor boli autoimune boală inflamatorie intestinală sindom Sjöngren Pancreas divisum Anomalii ale joncţiunii ductelor biliare şi pancreatice Pancreas inelar Coledococel Obstrucţie ampulară Litiază biliară Medicamente Hipercalcemie Hiperlipemie Boala grefă contra gazdă Toxine Compuşi organici PANCREATITELE EREDITARE Comfort şi Steinberg (1952) au sugerat pentru prima data cauza genetică arătând că pancreatita cronică poate să apară mai frecvent în anumite familii (8). Criteriile de diagnostic nu sunt universal acceptate, dar conform EUROPAC pancreatita ereditară este definită prin prezenţa a două rude de gradul I sau cel puţin trei rude de gradul II, în două sau mai multe generaţii, cu pancreatită cronică la care nu s-a identificat altă etiologie. Au fost identificaţi 6 factori de risc genetic responsabili de susceptibilitatea pentru pancreatită: tripsinogenul cationic (PRSS1), tripsinogenul anionic (PRSS2), serine protease inhibitor Kazal 1 (SPINK1), cystic fibrosis transmembrane con ductance reglator (CFTR), chymotrypsinogen C (CTR) şi calcium-sensing receptor (CASR) (9). Mutaţiile PRSS1 Howes şi colab. au constatat că 81,25% dintre familiile cu pancreatită ereditară au mutaţii PRSS1 (10). Genele PRSS1 şi PRSS2 au fost identificate în 1996 de Whitcomb şi colab. care au determinat secvenţa celor 5 exoni utilizând ADN genomic de la pacienţii cu pancreatită ereditară (11). Cele mai frecvente mutaţii sunt R22H şi N291. Aceste mutaţii perturbă în pancreas balanţa dintre proteaze şi inhibitorii lor determinând autodigestia organului (12). Gena PRSS1 este localizată 7q35 şi până în prezent au fost identificate 9 mutaţii. Mutaţia R122H determină un defect de inactivare (autoliză) a tripsinei activate (11) şi creşte autoactivarea tripsinogenului (13). S-a arătat că mutaţia N29I nu are efect asupra activării tripsinei şi stabilităţii tripsinogenului, dar s-a sugerat că este responsabilă de modificările ce apar în structura tripsinei, rezultând scăderea legării SPINK1 şi creşterea autoactivării. Modificările secvenţei peptidului N-terminal al tripsinogenului cationic cresc rata sa de degradare; mutaţiile A16V, D22G şi K23R pot determina creşterea autoactivării tripsinogenului în tripsină. Mutaţia 228delTCC amplifică transcripţia tripsinogenului, crescând astfel activitatea. Deşi iniţial s-a considerat că, de asemenea, mutaţiile PRSS2 se asociază cu predispoziţia pentru pancreatită, recent au fost publicate rezultate surprinzătoare ale unor studii care au demonstrat că o mutaţie PRSS2 (G191R) ar diminua activitatea tripsinei intrapancreatice şi ar proteja faţă de PC (14). Sunt afecţiuni rare cu transmitere autozomal dominantă cu penetranţă aproximativ 80%. Manifestările clinice apar precoce, de la vârsta de 10 ani; la majoritatea cazurilor PC se constituie după vârsta de 20 de ani. Copiii prezintă dureri abdominale recurente. Episoadele de pancreatită severă sunt rare. S-a demonstrat că există risc de adenocarcinom pan creatic la adult de 50 de ori mai mare comparativ cu populaţia generală. Riscul este crescut semnificativ la fumători. Mutaţiile SPINK1 Gena inhibitorului tripsinogenului cationic (SPINK1) este localizată pe cromozomul 5 (5q32); cea mai frecventă mutaţie este N34S. Moleculele SPINK1 sunt sintetizate în celulele acinare ale pancreasului şi sunt multifuncţionale; inhibă activitatea tripsinei şi au rol în reglarea autofagiei. Perturbarea balanţei intra pancreatice dintre tripsina şi activitatea SPINK1 poate fi responsabilă de apariţia pancreatitei. Se consideră că mutaţiile genei SPINK1 afectează legarea SPINK1 de tripsină şi sunt responsabile de inducţia autofagiei (15). Pancreatita ereditară determinată de mutaţii SPINK1 nu se asociază cu risc crescut de cancer pancreatic la adulţi. În perioada la Spitalul din Nantes au fost internaţi 10 copii cu diagnosticul de pancreatită ereditară: la 8 pacienţi au fost identificate mutaţii PRSS1 şi la 2 pacienţi mutaţii SPINK1. Au fost urmăriţi în medie 5,5 ani, perioadă în care nici un pacient nu a dezvoltat insuficienţă pancreatică (16). Mutaţiile CFTR. În 1998 s-a sugerat o legătură între mutaţiile genei responsabile de apariţia fibrozei chistice CFTR (cystic fibrosis trans membrane conductance regulator) şi pancreatita idiopatică.

4 239 Este bine cunoscut faptul că pancreasul reprezintă unul dintre organele cel mai mult afectate de disfuncţia CFTR, dar caracteristică este insuficienţa pancreatică exocrină, în timp ce pancreatita simptomatică este mult mai rar raportată. Pancreatită simptomatică apare la 1-2% dintre pacienţii cu fibroză chistică. La aceşti pacienţi se constată suficienţă pancreatică la naştere, dar par să dezvolte insuficienţă pancreatică mai curând decât pacienţii cu suficienţă pancreatică fără pancreatită. Conform unui studiu multicentric (2005), care a inclus pacienţi cu fibroză chistică din 29 de ţări, pancreatita la pacientul cu fibroză chistică este rară (1,24%), dar diferă în rândul acestora în funcţie de statusul funcţiei pancreatice: incidenţa este 10,3% la cei cu funcţie pancreatică păstrată şi este mult mai mică (0,5%) în rândul celor cu insuficienţă pancreatică (17). Sojo Aguirre şi colab. (2011) ra portează un procent mai mare de cazuri cu pan creatită (unul sau mai multe episoade de pancreatită) identificat la 520 de bolnavi cu fibroză chistică (18). Pacienţii afectaţi sunt frecvent heterozigoţi cu 2 mutaţii minore sau o mutaţie majoră şi o mutaţie minoră. Mutaţia R117H a fost mai frecvent raportată la pacienţii cu pancreatită. Genotipurile asociate cu efecte fenotipice uşoare au un risc mai mare de a genera pancreatită comparativ cu genotipurile asociate cu manifestări moderate/severe de fibroză chistică (19). Transheterozigoţii au risc semnificativ crescut de a dezvolta PC (20). Subiecţii cu mutaţii CFTR care nu generează fibroză chistică au risc mai mic de a avea PC. Mutaţiile CFTR nu se asociază cu risc crescut de cancer pancreatic. Pancreatita autoimună a fost definită în 1995 de Yoshida care a descris un caz de pancreatită cu mărire difuză a pancreasului şi îngustare neregulată a ductelor pancreatice, asociată cu hiper gamma globulinemie, anticorpi antinucleari pozitivi şi care a răspuns la corticoterapie (21). De fapt, se consideră că prima raportare îi aparţine lui Sarles (1961), care a descris pancreatită asociată cu icter obstructiv şi hipergammaglobulinemie ce sugera un mecanism imun (22). În 2001 Hamano şi colab. au constatat că nivelul seric al Ig G4 este crescut în pancreatita autoimună (23). Dar Ig G4 nu este numai un marker serologic, căci s-a demonstrat că pancreasul este infiltrat cu plasmocite Ig G4. Un aspect histologic asemănător a fost descris şi în alte organe astfel încât s-a propus termenul de boală asociată cu Ig G4 (Ig G4 related disease). Publicaţii recente iau în discuţie două subtipuri de pancreatită autoimună. Forma clasică este denumită pancreatită autoimună tip I şi se caracterizează prin niveluri serice Ig G4 crescute şi infiltrare tisulară cu plasmocite Ig G4. Pancreatita autoimună tip 2 nu se asociază cu Ig G4, caracteristică fiind infiltrarea cu neutrofile a epiteliului ductelor pancreatice (24). Rolul pe care îl are Ig G4 în inducţia bolii nu fost elucidat. La adult reprezintă 2-4% dintre pancreatitele cronice. Apare la orice vârstă, dar mai frecvent după 50 ani. Afectează de două ori mai frecvent sexul masculin. Majoritatea bolnavilor sunt asimptomatici sau au simptome uşoare. Pot avea dureri abdominle recurente, rar pancreatită acută, simp tome legate de bolile asociate. Mai mult de jumătate dintre bolnavi asociază icter obstructiv determinat de mărirea capului pancreasului sau de îngroşarea peretelui ductelor pancreatice. Cazurile pediatrice sunt rare. Pacienţii tineri au adesea dureri abdo minale ca simptom iniţial şi prezintă creşterea amilazelor serice. Nivelul seric crescut al Ig G4 reprezintă cel mai specific şi mai sensibil test pentru diagnosticul pancreatitei autoimune tip 1. Totuşi s-a observat că la pacienţii pediatrici nivelul seric al Ig G este rar crescut (25). Totodată, se constată creşterea nivelului seric al Ig G, gammaglobulinelor şi în mai mică măsură al Ig E. Pot fi evidenţiaţi variaţi autoanticorpi, precum şi scăderea nivelului seric al complementului C3 şi C4. Investigaţiile imagistice demonstrează mărirea difuză a pancreasului, îngustarea difuză şi neregulată a ductului pancreatic principal. Uneori se pot con s- tata: îngustarea canalului biliar comun cu disfuncţie hepatică colestatică, rare calcificări pancreatice sau formaţiuni chistice. Examenul histologic evidenţiază leziuni de fibroză cu infiltraţie limfoplasmocitară difuză în pancreas. Ocazional este întâlnită asocierea cu alte boli autoimune. Criteriile de diagnostic pentru copii nu sunt precizate (26). Tratamentul de bază este reprezentat de corticosteroizi administraţi oral. Majoritatea pacienţilor au răspuns bun la corticoterapie. PANCREATITE CRONICE OBSTRUCTIVE În etiologia PC diagnosticate la copil pot fi identificate cauze obstructive. Pancreatitele cronice obstructive sunt determinate de factori mecanici congenitali sau dobândiţi: malformaţii biliopancreatice sau litiază (Fig. 1). Anomaliile congenitale includ: pancreas divisum, pancreas inelar, coledococel. Malformaţia ductelor pancreatice cunoscută sub numele de pancres divisum este frecventă în populaţia generală (până la 10%) şi a fost raportată

5 240 în 12-50% din cazurile de pancreatită acută idiopatică la copil (Fig. 2). Deşi relaţia cauză-efect dintre pancreas divisum şi pancreatită este controversată, asocierea celor două entităţi este evidentă. Rezultă din lipsa de fuziune a ductelor pancreatice dorsal şi ventral. Cea mai mare parte a glandei drenează prin ductul dorsal (ductul Santorini) în papila minor, care are dimensiuni mici. Ductul ventral (Wirsung), care se deschide în papila major, drenează numai pancreasul ventral. Simptome de pancreatită pot apărea şi la pacienţii cu o mică comunicare între ductele ventral şi dorsal, care drenează separat în duoden reprezentând o variantă anatomică (sindromul ductului dorsal dominant). Obstrucţia cronică a canalelor pancreatice duce la dialatarea acinilor, cu ruperea acestora şi FIGURA 1. Pacientă în vârstă de 6 ani Pancreatită cronică malformaţie de ducte pancreatice şi litiază pancreatică (colangiopancreatografi e RM: Wirsung dilatat, decalibrare bruscă la nivelul capului pancreasului) Spitalul Clinic de Urgenţă pentru Copii Grigore Alexandrescu eliberarea enzimelor, având drept consecinţă autodigestie pancreatică cu leziuni ireversibile. Totuşi, existenţa acestei malformaţii, pancreas divisum, nu pare să fie suficientă pentru a genera PC şi se consideră că sunt necesari şi alţi factori, cum ar fi factorii genetici. În studiul efectuat, Bertin şi colab. au constatat că frecvenţa pancreas divisum a fost mai mare la pacienţii adulţi cu pancreatită ce asociau mutaţii CFTR comparativ cu pacienţii cu pancreatită alcoolică sau idiopatică, pancreatită asociată mutaţiilor genelor PRSS1 sau SPINK1 (27). Pancreasul inelar se asociază frecvent cu alte anomalii. Chistul de coledoc este mai frecvent raportat la adult şi generează mai rar complicaţii la copil (28). TRATAMENT Abordarea terapeutică include măsuri conservatoare (analgezice, antiinflamatorii, substituţie enzimatică), intervenţii endoscopice, precum şi proceduri chirurgicale. ERCP este utilizată ca procedură terapeutică pentru boala biliopancreatică ce generează pancreatită recurentă sau cronică. Un studiu recent care a analizat eficienţa ERCP comparativ cu eficienţa tratamentului chirurgical în managementul PC la copil a arătat o frecvenţă mai scăzută a recurenţelor şi a spitalizărilor la pacienţii la care s-a recurs la tratament chirurgical. Studiul publicat în 2001 de Weber a evaluat beneficiile tratamentului chirurgical în pancreatita cronică la copil. Au fost incluşi pacienţi cu PC la care terapia conservatoare s-a soldat cu eşec, necesitând tra tament antialgic cronic. La aceştia tratamentul chirurgical a oferit remisiune pe termen lung. Pancreatectomia distală cu pancreatico-jejunostomie pe ansă în Y a la Roux a înregistrat rezultate mai bune decât pancreatico-jejunostomia longitudinală (29). La cazurile de PC la care modalităţile terapeutice menţionate se dovedesc ineficiente se poate recurge la pancreatectomie totală cu autotransplant portal de insule pancreatice. Se constată ameliorarea durerii şi îmbunătăţirea calităţii vieţii, cu obţinerea independenţei faţă de insulină la jumătate din cazurile pediatrice (30). CONCLUZII FIGURA 2. Pacientă în vârstă de 11 ani Pancreatită cronică mutaţie CFTR şi pancreas divisum (colangiopancreatografi e RM: duct Wirsung cu dilataţii moniliforme şi duct Santorini la nivel cefalic ce nu confl uează, cu deschidere la nivelul duodenului separat) Spitalul Clinic de Urgenţă pentru Copii Grigore Alexandrescu Pancreatita cronică este rar întâlnită la copil, dar poate avea risc evolutiv sever. Întrucât dovezile his tologice se obţin cu dificultate, diagnosticul PC la copil se bazează pe criterii clinice, funcţionale şi morfologice. La pacienţii pediatrici, etiologia PC este diferită comparativ cu pacienţii adulţi; sunt

6 241 mai frecvent implicate cauze genetice şi anomalii structurale biliopancreatice. Recent a fost definită pancreatita autoimună, entitate care a fost raportată şi la copil. Abordarea terapeutică este complexă (măsuri conservatoare, intervenţii endoscopice, proceduri chirurgicale), dar uneori decepţionantă, fiind necesară pancreatectomia totală. Chronic pancreatitis in children Gabriela Lesanu 1, Daniela Pacurar 1, Cristina Becheanu 1, Raluca Vlad 1, Mariana Coman 2, Dumitru Oraseanu 1 1 Grigore Alexandrescu Emergency Children s Hospital, Bucharest 2 Marie Curie Emergency Children s Hospital, Bucharest ABSTRACT Chronic pancreatitis (CP) is characterised by chronic infl ammation, progressive fi brosis, pain and loss of endocrine and exocrine functions. In 1999 the hypothesis of sentinel acute pancreatitis event SAPE was formulated. This suggests that the initial episode of acute pancreatitis generated by metabolic or oxidative stress is followed by recurrent or chronic infl ammation which will fi nally lead to fi brosis. The pancreatic stellate cells have a key role in the progression of chronic pancreatitis and in the initiation of fi brinogenesis. CP is a heterogenous disese with a clinical picture that includes pain, endocrine and exocrine pancreatic dysfunction and various complications that might implicate adjacent organs. For the diagnosis of CP in adults histological, morphological criteria or a combination of clinical, functional and morphological arguments are needed. Recently the International Study Group Of Pediatric Pancreatitis proposed a set of diagnostic criteria for CP: (a) typical abdominal pain plus characteristic imagistic fi ndings or (b) exocrine pancreatic failure plus imagistic fi ndings or (c) endocrine pancreatic failure plus imagistic fi ndings. The etiology of CP is different in children compared to adult patients. Lately remarkable progress was made in the knowledge of hereditary and autoimmune pancreatitis. Obstructive causes may be identifi ed in CP in children. Chronic obstructive pancreatitis are determined by congenital or acquired mechanical factors. The therapy includes: conservative measures (analgesia, antiinfl ammatory medication, enzyme substitution), endoscopic interventions and surgical procedures. Endoscopic retrograde cholangiopancreatography is used as therapeutic procedure for biliopancreatic disease with recurrent or chronic pancreatitis. In patients with no response to any of this therapeutic measures total pancreatectomy and self transplantation of pancreatic islets may be tried. Key words: pancreatitis, pancreatic stellate cells INTRODUCTION Pancreatitis is the inflammation of the pancreas and may be considered an entity with a large clinical spectrum ranging from an acute isolated episode to chronic pancreatitis (CP) (1). We speak of acute pancreatitis when the episode has sudden onset and a duration shorter than 6 months; it has a specific cause, but the severity and the length of the course of disease are variable. Acute pancreatitis is a reversible process, with no long term effects on the pancreatic tissue and function. Recurrent pancreatitis is characterised by repeated episodes of pancreatitis ( 2) separated by a remission period; this points to an underlying susceptibility or intrinsic cause. CP has a disease course of more than 6 months and is characterised by chronic inflammation, progressive fibrosis, pain and loss of endocrine and exocrine functions. CP is the outcome for the situation when inflammation and tissue necrosis continue (2). In adults the incidence of CP is / in USA and 7.74/ in France (3). The incidence of CP in children is not known. PATHOGENESIS In 1999 the hypothesis of sentinel acute pancreatitis event SAPE was formulated. This suggests that the initial episode of acute pancreatitis generated by metabolic or oxidative stress is followed by recurrent or chronic inflammation

7 242 which will finally lead to fibrosis (4). The pancreatic stellate cells have a key role in the progression of chronic pancreatitis and in the initiation of fibrinogenesis; they are activated during recurrent necroinflammatory episodes or directly by toxic factors. Masamune (2008) demonstrated that NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) generates reactive oxygen in the stellate cells, activating them (5). During pancreatitis episodes, the stellate cells, macrophages and activated lymphocytes infiltrate the parenchyma, release cytokines and deposit small quantities of collagen. In some patients the inflammatory and stellate cells remain active and eventualy lead to pancreatic fibrosis. Inhibiting or remodelling these stellate cells may represent a future way of intervention for patients with CP. Michalski and colab. (2007) studied the coculture of pancreatic stellate cells and blood mononuclear cells and demonstrated the increase in fibronectin secreted by the mononuclear cells as well as the increase in IL-6, MCP-1 (monocyte chemotactic protein-1), TGF-beta and ECM (extracellular matrix) proteins in pancreatic stellate cells (6). So infiltration with mononuclear cells observed in CP might act as a trigger (for the pancreatic stellate cells) in the initiation of inflammation and fibrosis. POSITIVE DIAGNOSIS CP is a heterogenous disese with a clinical picture that includes pain, endocrine and exocrine pancreatic dysfunction and various complications that might implicate adjacent organs. The patients may present with an isolated symptom or a complex clinical picture resulting from the pancreatic dysfunction. Most frequently the abdominal pain is the main symptom, intermittent or persistent, ranging in intensity from mild to severe. Exocrine pancreatic iinsuffficiency generates maldigestion with flatulence, diarrhea and steatorrhea and also nutritional deficiency with deficits of proteins and vitamins. Endocrine pancreatic iinsuffficiency starts with alterated glucose tolerance, but 48% of adult patients with CP develop type I diabetes. The diagnosis of chronic pancreatits requires at least one clinical criteria (pain, episodes of acute pan creatitis, steatorrhea, diabetes) or well esta blished complications (obstruction/stenosis of biliary ducts with jaundice, colestasis, duodenal obstruction/stenosis, pancreatic pseudocysts, ascitis, other complications involving the neighboring organs). These clinical criteria must be corroborated with imagistic studies demonstrating the anomaly (Table 1) TABLE 1. Imagistic criteria in CP Anomalies of the ducts irregularities of the main pancreatic duct or its branches ± intraluminal filling defects calculi obstruction (stenosis) dilatation of the pancreatic duct Anomalies of the parenchyma global or focal enlargement of the gland cysts calcifications For the diagnosis of CP histological, mor phological criteria or a combination of clinical, functional and morphological arguments are needed. Imagistic studies are performed for most patients and they prove the morphological anomalies, but histological evidence is rarely obtained. The ultrasound, CT examination, MR cholangio pan crea tography and endoscopic retrograde cholangio pancreatography (ERCP) evaluate the pancreatic mor phology. ERCP is the option of choice in evaluating pancreatic ducts. Exploring the pan creatic function may be an argument fo CP when revealing pancreatic failure. Recently the International Study Group Of Pediatric Pancreatitis proposed a set of diagnostic criteria for CP: (a) typical abdominal pain plus characteristic imagistic findings or (b) exocrine pancreatic failure plus imagistic findings or (c) endo crine pancreatic failure plus imagistic findings (7). ETIOLOGICAL FORMS OF PANCREATITIS The etiology of CP is different in children (Table 2) compared to adult patients. In children the genetic causes and the biliopancreatic congenital anomalies are more frequently involved in the etiology of chronic pancreatitis. Recently, the autoimmune pancreatitis was described, a situation rarely discovered in chi ldren. Hereditary pancreatitis Comfort si Steinberg (1952) suggested for the first time a genetic cause for pancreatitis demonstrating that CP is more frequent in some families (8). The diagnostic criteria are not unanimously accepted, but according to EUROPAC hereditary pancreatitis is defined when chronic pancreatitis with no other identifiable etiology was diagnosed in at least two first degree relatives or at least three second degree relatives, in two or more generations.

8 243 TABLE 2. Etiology of CP in children Gene c anomalies PRSS1 mutations SPINK1 mutations CFTR mutations Autoimmune Isolated autoimmune pancreatitis Autoimmune pancreatitis associated with other autoimmune disease Inflammatory bowel disease Sjongren Syndrome Obstruc ve causes Pancreas divisum Anomalies of the biliary or pancreatic duct junctions Annular pancreas Choledocal cysts Obstruction of the ampula Gallstones Toxic, metabolic causes Idiopathic Drugs Hipercalcemia Hiperlipemia Gra versus host disease Toxins Organic compounds Six risk factors for genetic susceptibility for pancreatitis were identified: cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), serine protease inhibitor Kazal 1 (SPINK1), cystic fibrosis transmembrane conductance reglator (CFTR), chymotrypsinogen C (CTR) and calcium-sensing receptor (CASR) (9). PRSS1 mutations Howes and colab. observed that 81.25% of the families with hereditary pancreatits had PRSS1 mutations (10). PRSS1 and PRSS2 genes were identified in 1996 by Whitcomb and colab. Using genomic DNA from patients with hereditary pancreatitis, they described a 5 exons sequence (11). The most frequent mutations are R122H and N291. These mutations create an imbalance between pancreatic proteases and their inhibitors resulting in self digestion of tissue (12). PRSS1 gene is located on chromosome 7q35 and to the present day 9 mutations were described. R122H mutation has as a consequence a defect in the deactivation of active trypsin (11) increasing the self activation of trypsinogen (13). It has been showed that N29I mutation has no effect on activation of trypsin, nor on trypsinogen stability, but suggestions were made that it is responsible for the changes occuring in trypsin structure; this results in a poor binding of SPINK1 and an increase in self activation. The changes in the N-terminal peptide sequence of the cationic trypsinogen are increasing its degradation rate; mutations A16V, D22G and K23R may determine self activation of trypsinogen to trypsin. Mutation 228delTCC amplifies the transcription of trypsinogen, increasing its activation. Although initially it was also considered that PRSS2 mutations are associated to predisposition to develop pancreatitis, recently surprising data were published demonstrating that a mutation PRSS2 (G191R) reduces the activity of the pancreatic trypsin and protects from CP (14). These is rare pathology, with autosomal do minant inheritance and 80% penetrance. The clinical symptoms develop as early as 10 years of age; the majority of CP cases are diagnosed around 20 years of age. The children complain of recurrent abdominal pain. The severe episodes of pancreatitis are rare. There is a 50 fold increase in the risk of pancreatic adenocarcinoma in these patients. Smoking augments further more the risk. SPINK1 mutations The gene of the cationic trypsinogen inhibitor (SPINK1) is located on the fifth chromosome (5q32); the most frequent mutation is N34S. SPINK1 molecules are synthesized in the pancreatic acinar cells and have several functions: they inhibit the trypsin activity, play a role in the regulation of self digestion and stimulate growth. A pancreatic imbalance between trypsin and SPINK1 activity may be responsible for the onset of pancreatitis. It is considered that mutations of the SPINK1 gene affects SPINK1 binding to trypsin resulting in self digestion (15). Hereditary pancreatitis due to SPINK1 mutations is not associated with an increased risk of pancreatic cancer in adults. Between 1995 and 2007 in Nantes Hospital 10 children diagnosed with hereditary pancreatitis were admitted; PRSS1 and SPINK1 mutations were identified in 8 and 2 patients respectively. The follow-up was conducted on a mean of 5.5 years period: none of them developed pancreatic failure (16). CFTR mutations In 1998 a link between the mutations of the gene responsible for cystic fibrosis - CFTR (cystic fibrosis transmembrane conductance regulator) and idio pathic pancreatitis was suggested. The pancreas is known to be one of the most affected organs in CFTR dysfunction, but pancreatic exocrine insuffficiency is typical, while symptomatic pancreatitis is rare. The latter is diagnosed in only 1-2% of patients with cystic fibrosis. These particular patients have a good pancreatic function at birth, but they seem to develop pancreatic failure sooner than patients with normal pancreatic function and no pancreatitis. According to a multicenter study (2005) that included patients with cystic fibrosis from 29 countries, pancreatitis in

9 244 these patients is rare (1.24%), but the prevalence varies among them according to the functional status of the pancreas, from 10.3% in patients with preserved pancreatic function to much lower (0.5%) in patients with pancreatic failure (17). Sojo Aguirre et al. (2011) reported a large number of pancreatitis cases (one ore more episodes) in 520 cystic fibrosis patients (18). The patients affected are frequently heterozygotes with two minor or one major and one minor mutations. R117H mutation was more often reported in cystic fibrosis patients with pancreatitis. The genotypes associated with milder phenotypes have a greater risk of developing pancreatitis than the genotypes with moderate/severe manifestations of cystic fibrosis (19). Transheterozygots have highly increased risk for CP (20). Subjects with CFTR mutations that do not develop cystic fibrosis have low risk for CP. CFTR mutations do not increase the risk of pancreatic cancer. Autoimmune pancreatitis was defined in 1995 by Yoshida; he presented a case with diffuse pancreatic enlargement and irregular narrowing of the pancreatic ducts, associated with hypergammaglo bulinemia, positive antinuclear antibodies, that responded well to corticotherapy (21). In fact the first report seems to be attributed to Sarles (1961) who had a case of pancreatitis and obstructive jaundice with hypergammaglobulinemia that suggested an immune mechanism (22). In 2001 Hamano and colab. observed that seric Ig G4 level is raised in autoimmune pancreatitis (23). Ig G4 is not only a serologic marker, but also the pancreas is infiltrated with Ig G4 plasmocytes. Similar histologic findings were described in other organs so the term Ig G4 related disease was proposed. Recent articles discuss two types of autoimmune pancreatitis. The classic form is autoimmune pancreatitis type I and is characterised by increased seric Ig G4 and tissue infiltration with Ig G4 plasmocytes. Autoimmune pancreatitis type II is not associated with increased seric Ig G4; it is characterised by infiltration with neutrophiles of the pancreatic duct epithelia (24). The pathogenic role of Ig G4 in is not clear. In adults autoimmune pancreatitis represents 2-4% of all chronic pancreatitis. The onset may be at any age, but is more frequent after 50 years of age. It affects twice as frequent the male gender. Most of the patients have no or minor symptoms. Recurrent abdominal pain may be present, rarely acute pancreatitis, symptoms related to associated pathology. More than half the patients develop obstructive jaundice resulting from the enlargement of the head of the pancreas or the engorgement of the pancreatic duct wall. The pediatric cases are rare. Young patients complain often of abdominal pain initially and associate high seric amylases. The seric Ig G4 is the most sensible and specific test for autoimmune pancreatitis type I. Nevertheless in pediatric patients seric Ig G4 is rarely raised (25). At the same time it has been observed an increased seric level of Ig G, gammaglobulines and to a lesser extent Ig E. Several autoantibodies may be positive and C3 and C4 complement is low. Imagistic studies reveal a diffusely enlarged pancreas, diffuse and irregular narrowing of the main pancreatic duct. Sometimes the narrowing of the common bile duct is associated resulting in colestatic hepatic dysfunction; rarely pancreatic calcifications or cysts occur. The hystologic examination reveals fibrosis and diffuse lympho-plasmocytic infiltration in the pancreatic tissue. Sometimes other autoimmune disorders coexist. The diagnostic criteria in children are not properly established yet (26). The treatment relies on oral corticosteroids with good response in most of the cases. CHRONIC OBSTRUCTIVE PANCREATITIS Obstructive causes may be identified in CP in children. Chronic obstructive pancreatitis are determined by congenital or acquired mechanical factors: bilio-pancreatic malformations and lithiasis (Fig.1). Congenital anomalies include: pancreas divisum, annular pancreas, choledocal cyst. The malformation of pancreatic ducts known as pancreas divisum is rather frequent in the general population (up to 10%) and was reported in 12-50% cases of acute idiopathic pancreatitis in children (fig.2). Although the causal relationship between pancreas divisum and pancreatitis is controversial, the association is obvious. The anomaly results from lack of fusion of anterior and posterior pancreatic ducts. Most of the gland drains through the posterior duct (Santorini) in papila minor. The anterior duct (Wirsung), opening in papila major, drains only the anterior pancreas. Pancreatitis symptoms may appear in patients which have a small communication between the anterior and posterior ducts, ducts that drain separately in the duodenum. This represents an anatomical variant (dominant posterior pancreatic duct syndrome). Chronic obstruction of the pancreatic ducts leads to acinar dilation with acinar distruction and enzyme release, resulting in pancreatic self digestion with

10 245 irreversible lesions. Nevertheless, the existence of this anomaly, pancreas divisum, seems to be insufficient to generate CP and other factors are considered to concur, genetic factors for instance. In their study, Bertin and colab. observed that the incidence of pancreas divisum was higher in adult FIGURE 1. 6 years old female patient Chronic pancreatitis pancreatic duct malformation and lithiasis (MRCP: dilateted Wirsung, sudden narrowing at the head of the pancreas) Grigore Alexandrescu Emergency Children s Hospital Annular pancreas is frequently associated with other anomalies. Choledocal cyst is mostly an adult finding and rarely causes complications in children (28). TREATMENT The therapy includes: conservative measures (analgesia, antiinflammatory medication, enzyme substitution), endoscopic interventions and surgical procedures. ERCP is used as therapeutic procedure for biliopancreatic disease with recurrent or chronic pancreatitis. A recent study analized the efficacy of ERCP compaired to the surgical treatment in managing CP in children and showed a lower recurrence and hospitalization rate in patients that underwent surgery. The study published in 2001 in Arch Surgery by Weber evaluated the benefits of surgery in CP in children. Patients with no response to con servative treatment and which required chronic analgesia were included. For them surgical treatment offered long term remission. Distal pancreatectomy with Roux-en-Y duct-to-mucosa pancrea ticojejunos tomy had better results than longitudinal pan creaticojejunostomy (29). In patients with no response to any of this therapeutic measures total pancreatectomy and self transplantation of pancreatic islets may be tried. This releaves the pain and improves the quality of life; half the pediatric patients become insulin independent (30). CONCLUSIONS FIGURE years old female patient Recurrent hereditary pancreatitia CFTR mutation and pancreas divisum (colangio MR: Wirsung duct with moniliform dilations that does not converge together with Santorini duct into a common duct, separate opening in the duodenum) Grigore Alexandrescu Emergency Children s Hospital patients with pancreatitis which associated CFTR mutations as opposed to patients with alcoholic or idiopathic pancreatitis or pancreatitis associated PRSS1 or SPINK1 mutations (27). Chronic pancreatitis is a rare occasion in children, but may undertake a severe course of the disease. Considering histological evidence are difficult to obtain, the diagnosis in CP in children is based on clinical, functional and morphological criteria. The etiology in pediatric patients is different from adults; genetic factors and biliopancreatic congenital anomalies are more frequently involved. Recently, the autoimmune pancreatitis was described, a situation rarely discovered in children. The therapeutic approach is complex (con servative measures, endoscopic interventions and surgical procedures), but often dissapointing, complete pancreatectomy being requiered.

11 246 REFERENCES 1. Aoun E., Slivka A., Papachristou D.J. et al. Rapid evolution from the first episode of acute pancreatitis to chronic pancreatitis in human subjects, JOP, 2007; 8(5):573-8; 2. Lankisch P.G., Banks P.A. Pancreatitis, Springer, 1998; 3. Lévy P., Barthet M., Mollard B.R. et al. Estimation of the prevalence and incidence of chronic pancreatitis and its complications, Gastroenterol Clin Biol., 2006; 30(6-7):838-44; 4. Whitcomb D.C. Hereditary pancreatitis: new insights into acute and chronic pancreatitis, Gut,1999; 45: ; 5. Masamune A., Watanabe T., Kikuta K. et al. NADPH oxidase plays a crucial role in the activation of pancreatic stellate cell, Am J Physiol Gastrointest Liver Physiol., 2008; 294(1):G99-G108; 6. Michalski C,W,, Gorbachevski A,, Erkan M,, et al. Mononuclear cells modulate the activity of pancreatic stellate cells which in turn promote fibrosis and inflammation in chronic pancreatitis, J Transl Med, 2007; 5:5:63; 7. Morinville V.D., Husain S.Y., Bai H., et al. Definitions of Pediatric Pancreatitis And Survey Of Current Clinical Practices: Report From Insppire (International Study Group Of Pediatric Pancreatitis: In Search For A Cure), J Pediatr Gastroenterol Nutr; 2012:8:123-34; 8. Comfort M.W., Steinberg A.G. Pedigree of a family with hereditary chronic relapsing pancreatitis; Gastroenterology; 1952; 21:54 63; 9. Whitcomb D.C. Genetic aspects of pancreatitis; Annu Rev Med; 2010; 61:413-24; 10. Howes N., Lerch M.M., Greenhalf W. et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe; Clin Gastroenterol Hepatol; 2004; 2:252-61; 11. Whitcomb D.C., Gorry M.C., Preston R.A., et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene; Nat Genet; 1996; 14(2):141-5; 12. Rosendahl J., Bödeker H., Mössner J. et al. Hereditary chronic pancreatitis; Orphanet J Rare Dis; 2007; 4;2:1; 13. Sahin-Tóth M., Tóth M. Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen; Biochem Biophys Res Commun; 2000; 19;278(2):286-9; 14. Witt H., Sahin-Tóth M., Landt O. et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis; Nat Genet; 2006; 38(6):668-73; 15. Ohmuraya M., Sugano A., Hirota M. et al. Role of Intrapancreatic SPINK1/Spink3 Expression in the Development of Pancreatitis; Front Physiol; 2012; 3:126; 16. Schmitt F., Le Henaff G., Piloquet H. et al. Hereditary pancreatitis in children: surgical implications with special regard to genetic background; J Pediatr Surg; 2009; 44: ; 17. De Boeck K., Weren M., Proesmans M. et al. Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype; Pediatrics; 2005; 115(4):e463-9; 18. Sojo Aguirre A., Martínez Ezquerra N. et al. Pancreatitis in cystic fibrosis: association with genotype and pancreatic status; An Pediatr; 2011; 78:235-51; 19. Ooi C.Y., Durie P.R. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis; J Cyst Fibros; 2012; 5:17-20; 20. Rosendahl J., Landt O. et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?; Gut; 2012; 84:39-56; 21. Yoshida K., Toki F., Takeuchi T. et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis; Dig Dis Sci; 1995; 40: ; 22. Sarles H., Sarles J.C., Muratore R. et al. Chronic inflammatory sclerosis of the pancreas - an autonomous pancreatic disease?; Am J Dig Dis; 1961; 6:688-98; 23. Hamano H., Kawa S. et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis; N Engl J Med; 2001; 8;344(10):732-8; 24. Chari S.T., Kloeppel G., Zhang L. Histopathologic and clinical subtypes of autoimmune pancreatitis: the honolulu consensus document; Pancreatology; 2010; 10(6):664-72; 25. Takase M., Imai T., Nozaki F. et al. Relapsing autoimmune pancreatitis in a 14-year-old girl; J Nihon Med Sch; 2010; 77(1):29-34; 26. Friedlander J., Quiros J.A., Morgan T. et al. Diagnosis of Autoimmune Pancreatitis vs Neoplasms in Children with Pancreatic Mass and Biliary Obstruction; Clin Gastroenterol Hepatol; 2012;12: ; 27. Bertin C., Pelletier A.L., Vullierme M.P. et al. Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations; Am J Gastroenterol; Saluja S.S., Nayeem M., Sharma B.C. et al. Management of choledochal cysts and their complications; Am J Surg; 2012; 78(3):284-90; 29. Weber T.R., Keller M.S. Operative management of chronic pancreatitis in children; Arch Surg; 2001; 136(5):550-4; 30. Sutherland D.E., Radosevich D.M. et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis; J Am Coll Surg; 2012; 214(4):

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